The present invention relates to a novel concept in immunotherapy, by which deception of the immune system results in specific and most efficient destruction of cells of interest, cancer cells in particular.
There is strong, evidence that tumor progression in cancer patients is controlled by the immune system. This conclusion is based on observations that tumor progression is often associated with secretion of immune suppressive factors and/or downregulation of MHC class I antigen presentation functions (1-5). The inference is that tumors must have elaborated strategies to circumvent an apparently effective immune response. Importantly, a tumor-specific immune response can be detected in individuals (6-8).
The apparent inefficiency of anti tumor immune responses that results in failure to combat the disease laid the foundation to current concepts of immunotherapy. It is suggested that boosting the anti-tumor immune response by deliberate vaccination or by other immunotherapeutic approaches may increase the potential benefits of immune-based therapies (6, 9-11).
The MHC class I-restricted CD8 cytotoxic T cell (CTL) effector arm of the adaptive immune response is best equipped to recognize the tumor as foreign and initiate the cascade of events resulting in tumor destruction (12,13). Therefore, the most attractive approach in cancer immunotherapy is centered on vaccination strategies designed to enhance the CTL arm of the antitumor response and consequently overcome the mechanisms of tumor escape from CTL (9-11).
One of the best-studied escape mechanisms by which tumor cells evade immune attack is by downregulation of the MHC class I molecules which are so the antigens recognized by CTLs (1-5,14).
Mutations along the class I presentation pathway should be the simplest way for tumors to escape CTL-mediated elimination since it can be achieved by one or two mutational events (two mutations to inactivate both alleles or one mutation to create a dominant negative inhibitor) (1-3).
Downregulation of MHC class I expression is frequently observed in human tumors, and is particularly pronounced in metastatic lesions (3, 14-17). This is circumstantial but nevertheless compelling evidence of the role of CTL in controlling tumor progression in cancer patients. MHC class I expression has been mainly analyzed in surgically removed tumor specimens using immunohistochemical methods (14-15). Partial reduction or complete loss of MHC have been reported, encompassing all MHC molecules or limited to particular alleles (14-15). MHC loss can be seen in some but not all lesions of the same patient. Downregulation of MHC class I expression has been attributed to mutations in β2-microglobulin (β2-m), transporter associated with antigen presentation (TAP) proteins, or the proteosomal LMP-2 and LMP-7 proteins (2, 18-21). Additional evidence implicating loss of MHC class I expression as a mechanism for tumor escape from CTL-mediated elimination comes from a longitudinal study of a melanoma patient. Tumor cells removed during initial surgery presented nine different antigens restricted to four separate HLA class I alleles to CTL clones established from the patient (1). The patient remained disease free for 5 years after which a metastasis was detected. Notably, a cell line established from the metastatic lesion had lost all four alleles that had previously been shown to present melanoma antigens.
Thus, the downregulation of class I MHC molecule is a severe limiting problem for cancer immunotherapy and the application of anti-cancer vaccines. There is thus a widely recognized need for, and it would be highly advantageous to have, an novel approach of immunotherapy devoid of the above limitations, namely an approach of immunotherapy which is independent of the level of expression of MHC class I molecules by cancer cells.